Deposition of dense plaques and the presence of neurofibrillary tangles are two postmortem criteria used in the definitive diagnosis of Alzheimer's disease. The major component of the dense plaques is a 40 amino acid beta-amyloid peptide that is derived from a larger amyloid protein precursor (APP). Two alternative pathways have been suggested in the processing of APP, only one of which produces the beta-amyloid peptide. The function of APP and its different cleavage products are still poorly understood. Furthermore, the pathways in which the proteins function have not been identified. A family of APP- related proteins is present in mammals. Knockout of the APP family in mice leads to postnatal lethality and type II lissencephaly, indicating that the APP family has essential functions during development. We are interested in studying the function of APP and are approaching this problem by examining an APP- related gene in a simple model system, the nematode Caenorhabditis elegans. C. elegans has the experimental advantages of being easy to manipulate genetically and being able to generate transgenic animals quickly. We have identified a C. elegans gene, apl-1, that encodes an APP-related protein. APL- 1 has strong sequence homology and structural similarities with the APP family proteins. Knockout of apl-1 leads to larval lethality, which can be rescued by germline transformation of a apl-1 genomic fragment. Interestingly, the apl-1 lethality can also be rescued by transformation with constructs encoding only the extracellular domain of APL-1 or driving pan-neural expression of APL-1. High levels of APL-1 overexpression lead to an incompletely penetrant larval lethality, suggesting that levels of APL-1 must be tightly regulated. We propose to: 1) determine in which cells apl-1 must be expressed to rescue the lethality; 2) determine whether APL-1 is required during later developmental stages; 3) elucidate the underlying basis of the lethality in APL-1 overexpression animals; 4) identify how elevated temperatures affect APL-1 function; and 5) identify genes that act in the APL-1 pathway. C. elegans provides a tractable genetic model in which many approaches not feasible for use in mammalian systems can be used to understand APL-1 function. Understanding the pathways through which APL-1 functions may give insights into the pathways through which human APP functions. PUBLIC HEALTH RELEVANCE: Alzheimer's disease affects over 4.5 million Americans. Mutations in three genes, including the Amyloid Precursor Protein (APP) gene, have been correlated with familial Alzheimer's disease. However, the function of APP is still unknown. We are examining an APP-related gene in a genetic model system, the roundworm Caenorhabditis elegans; information from C. elegans is likely to provide clues into the normal function of APP in higher organisms, such as man.